Use of reboxetine to treat narcolepsy

ABSTRACT

Described herein are methods of treating narcolepsy with cataplexy, comprising administering reboxetine to a human being in need thereof. Reboxetine may also be used in the manufacture of a medicament for the treatment of narcolepsy with cataplexy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of International PatentApplication No. PCT/US2019/056134, filed Oct. 14, 2019; which claims thebenefit of U.S. Provisional Patent Application No. 62/745,956, filedOct. 15, 2018; this application also claims the benefit of U.S.Provisional Patent Application Nos. 62/943,077, filed Dec. 3, 2019; and62/946,295, filed Dec. 10, 2019; all of these priority applications areincorporated by reference herein in their entirety.

BACKGROUND

Narcolepsy is a serious and debilitating neurological condition thatcauses dysregulation of the sleep-wake cycle and is characterizedclinically by excessive daytime sleepiness (EDS), cataplexy, hypnagogichallucinations, sleep paralysis, and disrupted nocturnal sleep.Narcolepsy is estimated to afflict an estimated 185,000 individuals inthe U.S. Cataplexy is seen in an estimated 70% of narcolepsy patientsand is a sudden reduction or loss of muscle tone while a patient isawake, typically triggered by strong emotions such as laughter, fear,anger, stress, or excitement. Type 1 narcolepsy includes cataplexy,while Type 2 narcolepsy does not include cataplexy. Narcolepsyinterferes with cognitive, psychological, and social functioning,increases the risk of work- and driving-related accidents, and isassociated with a 1.5 fold higher mortality rate. Depression is reportedin up to 57% of patients. The debilitating effects of narcolepsy are farreaching for the estimated nearly 200,000 patients living with thisdisorder in the United States. Narcolepsy interferes with mental andsocial functioning, increases work and driving related accidents, andresults in a nearly two-fold higher mortality rate. Unfortunately,currently approved treatments are few for this under-diagnosed orphancondition and are limited by variability in efficacy from patient topatient, tolerability issues and the need for DEA scheduling.

SUMMARY

Described herein are methods of treating narcolepsy with cataplexy,comprising administering an antidepressant, such as a selectivenorepinephrine inhibitor, e.g. atomoxetine, edivoxetine, or reboxetine,to a human being in need thereof.

Some embodiments include use of an antidepressant, such as a selectivenorepinephrine inhibitor, e.g. atomoxetine, edivoxetine, or reboxetine,in the manufacture of a medicament for the treatment of narcolepsy withcataplexy.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising an antidepressant, such as a selective norepinephrineinhibitor, e.g. atomoxetine, edivoxetine, or reboxetine, andinstructions to use the pharmaceutical composition to treat narcolepsywith cataplexy in a human being.

In some embodiments, an antidepressant, such as a selectivenorepinephrine inhibitor, e.g. atomoxetine, edivoxetine, or reboxetine,is administered at least once daily for more than two weeks. In someembodiments, the human being experiences a reduction in the number ofcataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale(ESS) score, a reduction in the Maintenance of Wakefulness Test (MWT)score, a reduction in the Narcolepsy Symptom Assessment Score (NSAQ), areduction in the Patient Global Impression of Severity (PGI-S) score, ascore below 4 in the Patient Global Impression of Change (PGI-C), or areduction in the Hamilton Depression Rating Scale (HAM-D), orimprovement in the ability to concentrate (e.g. on the NSAQ) as a resultof the treatment.

Some embodiments include a method of improving the ability toconcentrate comprising administering an antidepressant, such as aselective norepinephrine inhibitor, e.g. atomoxetine, edivoxetine, orreboxetine, to a mammal or a human being in need thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the change in weekly cataplexy attacks for human patientswho received reboxetine and placebo as described in Example 22.

FIG. 2 depicts the number of human patients with a 50% or greaterreduction in weekly cataplexy attacks, where the human patients receivedreboxetine or placebo as described in Example 22.

FIG. 3 depicts the number of human patients with a 75% or greaterreduction in weekly cataplexy attacks, where the human patients receivedreboxetine or placebo as described in Example 22.

FIG. 4 depicts the change in Epworth Sleepiness Scale Score for humanpatients who received reboxetine and placebo as described in Example 22.

FIG. 5 depicts the change in weekly cataplexy attacks for human patientswho received reboxetine and placebo as described in Example 22.

FIG. 6 depicts the reduction in the weekly frequency of inadvertent napsfor human patients who received reboxetine and placebo as described inExample 22.

FIG. 7 depicts the number of human patients with a 50% or greaterreduction inadvertent naps, where the human patients received reboxetineor placebo as described in Example 22.

FIG. 8 depicts the improvement in the ability to concentrate score forhuman patients who received reboxetine and placebo as described inExample 22.

FIG. 9 depicts the number of human patients with a “very good” or “good”ability to concentrate, where the human patients received reboxetine orplacebo as described in Example 22.

DETAILED DESCRIPTION

An antidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin,fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline,amoxapine, desipramine, protriptyline, trimipramine, nortriptyline,maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine,trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine,escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine,mirtazapine, nefazodone, selegiline, sibutramine, milnacipran,tesofensine, brasofensine, moclobemide, rasagiline, nialamide,iproniazid, iproclozide, toloxatone, butriptyline, dosulepin,dibenzepin, iprindole, lofepramine, opipramol, norfluoxetine,dapoxetine, ketamine, etc., including a norepinephrine reuptakeinhibitor such as atomoxetine, edivoxetine, or reboxetine, have thepotential to treat the symptoms of narcolepsy.

Many antidepressants, such as norepinephrine reuptake inhibitors, e.g.atomoxetine, edivoxetine, or reboxetine, lack of DEA scheduling, whichwould represent a significant benefit to patients living with thiscondition.

A person may have Type 1 narcolepsy if Criteria A and B are met:

-   -   A. The patient has daily periods of irrepressible need to sleep        or daytime lapses into sleep occurring for at least 3 months    -   B. The presence of one or both of the following:        -   1. Cataplexy (as defined under Essential Features) and a            mean sleep latency of <8 minutes and ≥2 Sleep-Onset REM            Periods (SOREMPs) on a Mean Sleep Latency Test (MSLT)            performed according to standard techniques. A SOREMP (within            15 minutes of sleep onset) on the preceding laboratory-based            polysomnography (PSG) may replace one of the SOREMPs on the            MSLT        -   2. CSF hypocretin-1 concentrations measured by            immunoreactivity either <110 pg/mL or <⅓ of mean values            obtained in normal subjects with the same assay

In young children, narcolepsy may sometimes present as excessively longnight sleep or by resumption of previously discontinued daytime napping.If narcolepsy Type 1 is strongly suspected clinically but criteria B2are not met, a possible strategy is to repeat the MSLT

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, daily periods of irrepressible need to sleep or daytime lapsesinto sleep occurring for at least about 3 months, at least 4 months, atleast about 5 months, at least about 6 months, at least about 7 months,at least about 8 months, at least about 9 months, at least about 10months, at least about 11 months, at least about 12 months, at leastabout 13 months, at least about 14 months, at least about 15 months, atleast about 16 months, at least about 17 months, at least about 18months, at least about 2 years, at least about 3 years, at least about 4years, at least about 5 years, at least about 10 years, at least about15 years, at least about 20 years, at least about 25 years, at leastabout 30 years, at least about 40 years, at least about 50 years, atleast about 60 years, about 3-9 months, about 9-18 months, about 18months to about 2 years, about 2-5 years, about 5-10 years, about 10-15years, about 15-20 years, about 20-25 years, about 25-30 years, about30-35 years, about 35-40 years, about 40-50 years, about 50-60 years, ormore.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, a mean sleep latency of less than about 1 minute, less thanabout 2 minutes, less than about 3 minutes, less than about 4 minutes,less than about 5 minutes, less than about 6 minutes, less than about 7minutes, less than about 8 minutes, about 0.1-1 minutes, about 1-2minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1 minute, about2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6minutes, about 7 minutes, or about 8 minutes.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, at least 2, at least 3, or at least 4 SOREMPs on an MSLT (MeanSleep Latency Test) performed according to standard techniques. A SOREMPwithin 15 minutes of sleep onset on the preceding nocturnal PSG mayreplace one of the SOREMPs on the MSLT

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, CSF hypocretin-1 concentrations measured by immunoreactivitythat are less than about 40 pg/mL, less than about 50 pg/mL, less thanabout 60 pg/mL, less than about 70 pg/mL, less than about 80 pg/mL, lessthan about 90 pg/mL, less than about 100 pg/mL, less than about 110pg/mL.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, CSF hypocretin-1 concentrations measured by immunoreactivitythat are less than about 1/10, less than about 1/9, less than about ⅛,less than about 1/7, less than about ⅙, less than about ⅕, less thanabout ¼, or less than about ⅓ of mean values obtained in normal subjectswith the same assay.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may be, and/or may be selected for being,young children presenting with excessively long night sleep.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may be, and/or may be selected for being,young children presenting with resumption of previously discontinueddaytime napping.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, a diagnosis of narcolepsy with cataplexy that meets theInternational Classification of Sleep Disorders, Third Edition (ICSD-3)criteria.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, a cataplexy subscore on the Ullanlinna Narcolepsy Score (UNS)that is at least 1, at least about 2, at least about 3, at least about4, at least about 5, at least about 6, at least about 7, at least about8, at least about 9, at least about 10, about 11, about 1-2, about 2-3,about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about9-10, about 10-11, about 2-4, about 4-6, about 6-8, about 8-10, about2-6, or about 6-10, or any number between 1 and 11.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, a score on the Epworth Sleepiness Scale (ESS) that is at leastabout 10, greater than about 10, at least about 11, at least about 12,at least about 13, at least about 14, at least about 15, at least about16, at least about 17, at least about 18, at least about 19, at leastabout 20, at least about 21, at least about 22, at least about 23, atleast about 24, about 10-11, about 11-12, about 12-13, about 13-14,about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 10-13,about 13-16, about 16-19, about 19-22, or about 22-24.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, at least about 7, at least about 8, at least about 9, at leastabout 10, at least about 11, at least about 12, at least about 13, atleast about 14, at least about 15, at least about 16, at least about 17,at least about 18, at least about 19, at least about 20, at least about21, at least about 28, at least about 35, about 7-14, about 14-21, about21-28, about 28-35, about 35-49, or about 49-70 cataplexy attacks perweek.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine may have, and/or may be selected forhaving, a Maintenance of Wakefulness Test (MWT) score that is less thanabout 1 minutes, less than about 2 minutes, less than about 3 minutes,less than about 4 minutes, less than about 5 minutes, less than about 6minutes, less than about 7 minutes, less than about 8 minutes, less thanabout 9 minutes, less than about 10 minutes, less than about 11 minutes,less than about 12 minutes, less than about 13 minutes, less than about14 minutes, less than about 15 minutes, less than about 16 minutes, lessthan about 17 minutes, less than about 18 minutes, less than about 19minutes, less than about 20 minutes, about 0-1 minutes, about 1-2minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes,about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes,about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12minutes, about 12-16 minutes, about 16-20, or about 0-19 minutes.

In some embodiments, the patient has had, and/or may be selected forhaving had, symptoms of narcolepsy for about 1-5 years, about 5-10years, about 10-15 years, about 15-20 years, about 20-25 years, about25-30 years, about 30-35 years, about 35-40 years, about 40-45 years,about 45-50 years, about 50-55 years, about 55-60 years, about 60-65years, about 65-70 years, about 70-75, or more than 75 years prior toreceiving an antidepressant, including a norepinephrine inhibitor suchas reboxetine for treatment.

In some embodiments, the patient has, and/or may be selected for having,an age of about 0-5 years, about 5-10 years, about 10-15 years, about15-20 years, about 20-25 years, about 25-30 years, about 30-35 years,about 35-40 years, about 40-45 years, about 45-50 years, about 50-55years, about 55-60 years, about 60-65 years, about 65-70 years, about70-75, or more than 75 years prior to receiving an antidepressant,including a norepinephrine inhibitor such as reboxetine for treatment.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may be, and/or may be selected for being female. In someembodiments, the patient may be selected for being female, nonlactatingand nonpregnant.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may be, and/or may be selected for being male.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, anyconcomitant sleep disorder. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, any concomitant sleep disorder other thanmild sleep apnea (<15 events per hour) or mild to moderate sleep apnea(<30 events per hour) with stable treatment. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, any clinically significantconditions potentially causing EDS. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, any clinically significant psychiatricdisorders. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, any type of depression that was not caused by narcolepsy. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, any sleepinesscaused by depression that was not caused by narcolepsy. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, an affective disorder.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a psychiatricdisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a cerebral function disorder. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a movement disorder. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a dementia Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a motor neuron disease.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not be concurrently taking sodium oxybate. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot be concurrently taking a stimulant. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not be concurrentlytaking an anticonvulsant. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not be concurrently takingclonidine. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not be concurrently taking a selectiveserotonin reuptake inhibitor (SSRI). Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not be concurrentlytaking a serotonin and norepinephrine re-uptake inhibitor (SNRI). Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not be concurrently taking a monoamine oxidase inhibitor(MAOI). Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not be concurrently taking a tricyclicantidepressant (TCA). Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not be concurrently taking ahypnotic. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not be concurrently taking an anxiolytic. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not be concurrently taking a sedating antihistamine. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not be concurrently taking an antipsychotic. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot be concurrently taking any other medication for the treatment ofnarcolepsy or cataplexy.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, aneurodegenerative disease. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a seizure disorder. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a convulsive disorder. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a diagnosis of cancer (exceptpossibly basal cell carcinoma) within the last 5 years.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a bilirubinlevel more than 2 times the upper limit of normal. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, an alanine aminotransferase levelmore than 2 times the upper limit of normal. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, an aspartate aminotransferaselevel more than 2 times the upper limit of normal. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, an alkaline phosphatase levelmore than 2 times the upper limit of normal.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having clinicallysignificant hypertension. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having uncontrolled hypertension. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having a history of cardiovascular disease. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having myocardialinfarction. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving angina. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving disrhythmias. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having cardiac failure.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having a history ofnarrow angle glaucoma. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having gastric bypass. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having any condition that would be expected toaffect drug absorption.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, headaches.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a depression.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, majordepression. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a treatment resistant depression.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, treatmentresistant bipolar depression. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a bipolar disorder. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, cyclothymia. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a seasonal affectivedisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a mood disorder. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, chronic depression (e.g. dysthymia). Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a psychotic depression.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having a history ofpsychotic episodes. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having significant risk of self-injury, suicide, or aggressiontowards others.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a postpartumdepression. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a premenstrual dysphoric disorder (PMDD). Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a situational depression. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an atypicaldepression. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a mania. Some patients treated with an antidepressant, includinga norepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, an anxiety disorder. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, attention deficit disorder (ADD).

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, attentiondeficit disorder with hyperactivity (ADDH). Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, attention deficit/hyperactivitydisorder (AD/HD). Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a manic condition. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, an obsessive-compulsive disorder. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a bulimia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, obesity orweight-gain. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a chronic fatigue syndrome.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a premenstrualsyndrome. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a substance addiction or abuse. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a nicotine addiction. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a psycho-sexual dysfunction. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a pseudobulbaraffect. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, emotional lability.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an anxietydisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a phobia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a generalized anxiety disorder. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a social anxiety disorder. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a panicdisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for nothaving, an agoraphobia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, an obsessive-compulsive disorder. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, post-traumatic stress disorder(PTSD). Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a mania.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a manicdepressive illness. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a hypomania. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a unipolar depression. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a stress disorder. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a somatoform disorder.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a personalitydisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a psychosis.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, schizophrenia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a delusionaldisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a schizoaffective disorder. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a schizotypy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, aggression. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, aggression in Alzheimer's disease. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, agitation.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, agitation inAlzheimer's disease.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a drugdependence. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, addiction to cocaine. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, addiction to or dependence on apsychostimulant. Some patients treated with an antidepressant, includinga norepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, addiction to or dependence on crack. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, addiction to or dependence oncocaine. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, addiction to or dependence on speed. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, addiction to or dependence onmethamphetamine. Some patients treated with an antidepressant, includinga norepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, addiction to or dependence on nicotine.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, addiction toor dependence on alcohol. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, addiction to or dependence on an opioid. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, addiction to ordependence on an anxiolytic and/or a hypnotic drug. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for nothaving, addiction to or dependence on a cannabis (marijuana). Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, addiction toor dependence on an amphetamine. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, addiction to or dependence on ahallucinogen. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, an addiction to or dependence on phencyclidine.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, addiction toor dependence on a volatile solvent. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, addiction to or dependence on a volatilenitrite. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, senile dementia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, an Alzheimer's type dementia. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, memory loss. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, an amnesia/amnesticsyndrome. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, an apilepsy. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, disturbances of consciousness. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a coma. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a lowering of attention. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a speechdisorder. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a voice spasm. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, Parkinson's disease. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a Lennox-Gastaut syndrome. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, autism. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a hyperkineticsyndrome. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, schizophrenia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, had a stroke. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a cerebral infarction. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a cerebral bleeding. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a cerebralarteriosclerosis. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a cerebral venous thrombosis. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a head injury.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an akinesia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an athetosis.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an ataxia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a ballismus.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, ahemiballismus. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a bradykinesia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a cerebral palsy.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a chorea. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Huntington'sdisease. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a rheumatic chorea. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a Sydenham's chorea. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a dyskinesia. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a tardive dyskinesia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a dystonia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, ablepharospasm.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a spasmodictorticollis. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a dopamine-responsive dystonia. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, restless legs syndrome (RLS). Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a tremor. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, an essential tremor.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Tourette'ssyndrome. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, Wilson's disease.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a vasculardementia. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a dementia with Lewy bodies. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a mixed dementia. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a fronto-temporal dementia. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having,Creutzfeldt-Jakob disease. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a normal pressure hydrocephalus. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, Wernicke-Korsakoff Syndrome.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Pick'sdisease. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a progressive bulbar palsy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a primary lateral sclerosis (PLS). Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a progressivemuscular atrophy. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a post-polio syndrome (PPS). Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a spinal muscular atrophy (SMA).

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a spinal motoratrophy. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, Tay-Sach's disease. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a Sandoff disease. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a hereditary spastic paraplegia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Alzheimer'sdisease. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a prion-related disease. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a cerebellar ataxia. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a spinocerebellar ataxia (SCA).

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a spinalmuscular atrophy (SMA). Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a bulbar muscular atrophy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a Friedrich's ataxia. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, Lewy body disease. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, amyotrophic lateralsclerosis (ALS or Lou Gehrig's disease). Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, multiple sclerosis (MS). Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a multiple systematrophy.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Shy-Dragersyndrome. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a corticobasal degeneration. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a progressive supranuclear palsy.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, Wilson'sdisease. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, Menkes disease. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, an adrenoleukodystrophy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy (CADASIL). Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a musculardystrophy.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, aCharcot-Marie-Tooth disease (CMT). Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a familial spastic paraparesis. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, aneurofibromatosis. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, an olivopontine cerebellar atrophy or degeneration. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, astriatonigral degeneration. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, Guillain-Barr-syndrome. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, a spastic paraplesia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, epilepticseizures. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, nonepileptic seizures. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, epilepsy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, febrile seizures. Some patients treated withan antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, partial seizures. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, simple partialseizures. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, Jacksonian seizures. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, complex partial seizures. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, an epilepsia partialiscontinua. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, generalized seizures. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, generalized tonic-clonic seizures. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an absenceseizure.

Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, atonicseizures. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, myoclonic seizures. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, juvenile myoclonic seizures. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, infantile spasm. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, statusepilepticus. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, Rett Syndrome. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, a tinnitus. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, disturbances of consciousness disorders.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a sexualdysfunction. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a voice disorder due to uncontrolled laryngeal muscle spasms.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, an abductorspasmodic dysphonia. Some patients treated with an antidepressant,including a norepinephrine inhibitor such as reboxetine for narcolepsy(e.g. with cataplexy and/or EDS) may not have, and/or may be selectedfor not having, an adductor spasmodic dysphonia. Some patients treatedwith an antidepressant, including a norepinephrine inhibitor such asreboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have,and/or may be selected for not having, a muscular tension dysphonia.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, a vocaltremor. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a diabetic neuropathy. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a chemotherapy-induced neurotoxicity. Somepatients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, methotrexateneurotoxicity. Some patients treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine for narcolepsy (e.g. withcataplexy and/or EDS) may not have, and/or may be selected for nothaving, a stress urinary incontinence. Some patients treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, urge urinary incontinence. Some patientstreated with an antidepressant, including a norepinephrine inhibitorsuch as reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) maynot have, and/or may be selected for not having, fecal incontinence.Some patients treated with an antidepressant, including a norepinephrineinhibitor such as reboxetine for narcolepsy (e.g. with cataplexy and/orEDS) may not have, and/or may be selected for not having, erectiledysfunction.

Cataplexy includes a sudden reduction or loss of muscle tone while apatient is awake, which may affect specific parts of the body or theentire body, such as eyelids, head drop, facial sagging and/ortwitching, slurred speech, jaw weakness, weakness in arms, shoulders, orhands, and/or buckling of knees. Cataplexy may be pathognomonic fornarcolepsy. Cataplexy may be triggered by strong emotions, such aslaughter, elation, surprise, or anger. Cataplexy may be partial orlocalized (in about 75% of cases) and is usually of short duration. Thefrequency of cataplexy may vary widely. Narcolepsy with cataplexy may besocially disabling and isolating.

Some patients being treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine may have, and/or may beselected for having, narcolepsy with cataplexy (Type 1) that is anautoimmune disorder resulting in a loss of hypocretin (orexin)-producingneurons in the CNS. Hypocretins (orexins) are hypothalamic-specificpeptides with neuroexcitatory activity. A patient being treated with anantidepressant, including a norepinephrine inhibitor such as reboxetinefor narcolepsy with cataplexy is, and may be selected for being, apredisposed individual with specific genetic markers including humanleukocyte antigen (HLA DQB1/06:02) and/or T-cell receptor alphavariants. Some patients being treated with an antidepressant, includinga norepinephrine inhibitor such as reboxetine may not have, and may beselected for not having, narcolepsy associated with loss of hypocretinneurons. Some patients being treated with an antidepressant, including anorepinephrine inhibitor such as reboxetine may have, or may be selectedfor having, narcolepsy precipitated by seasonal Streptococcusinfections, H1N1 influenza, and/or H1N1 vaccination in geneticallypredisposed individuals.

Existing treatments for narcolepsy only address some of its symptoms,provide variable efficacy, and have significant side effects.Additionally, all existing treatments are controlled substances.

According to the FDA, “there is a continued need for additionaleffective and tolerable treatment options for patients to improve theirdaily functioning.” (The Voice of the Patient, A series of reports fromthe U.S. Food and Drug Administration's (FDA's) Patient-Focused DrugDevelopment Initiative, Narcolepsy, June 2014. p. 25)

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce daytimesleepiness by at least about 1%, at least about 5%, at least about 10%,at least about 20%, at least about 30%, at least about 40%, at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%,about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%,about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, orabout 75-100%, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, a selective serotonin reuptakeinhibitor (SSRI), or a selective norepinephrine reuptake inhibitor(SNRI)).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce cataplexy by atleast about 1%, at least about 5%, at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the number ofpartial cataplexy attacks by at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, at least about 1 per week, at least about 2 per week, at leastabout 3 per week, at least about 4 per week, at least about 5 per week,at least about 6 per week, at least about 7 per week, at least about 8per week, at least about 9 per week, at least about 10 per week, atleast about 12 per week, at least about 14 per week, at least about 16per week, at least about 18 per week, at least about 20 per week, atleast about 22 per week, at least about 24 per week, at least about 26per week, at least about 28 per week, at least about 30 per week, atleast about 40 per week, at least about 50 per week, about 1-2 per week,about 2-3 per week, about 3-4 per week, about 4-5 per week, about 5-6per week, about 6-7 per week, about 7-8 per week, about 8-9 per week,about 9-10 per week, about 10-11 per week, about 11-12 per week, about12-13 per week, about 13-14 per week, about 14-15 per week, about 15-16per week, about 16-17 per week, about 17-18 per week, about 18-19 perweek, about 19-20 per week, about 1-10 per week, about 10-20 per week,about 20-30 per week, about 30-40 per week, about 40-50 per week, about50-60 per week, or more, e.g. as compared to baseline, placebo, or someother appropriate control (including an active control, such as astimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the number ofcomplete cataplexy attacks by at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, at least about 1 per week, at least about 2 per week, at leastabout 3 per week, at least about 4 per week, at least about 5 per week,at least about 6 per week, at least about 7 per week, at least about 8per week, at least about 9 per week, at least about 10 per week, atleast about 12 per week, at least about 14 per week, at least about 16per week, at least about 18 per week, at least about 20 per week, atleast about 22 per week, at least about 24 per week, at least about 26per week, at least about 28 per week, at least about 30 per week, atleast about 40 per week, at least about 50 per week, about 1-2 per week,about 2-3 per week, about 3-4 per week, about 4-5 per week, about 5-6per week, about 6-7 per week, about 7-8 per week, about 8-9 per week,about 9-10 per week, about 10-11 per week, about 11-12 per week, about12-13 per week, about 13-14 per week, about 14-15 per week, about 15-16per week, about 16-17 per week, about 17-18 per week, about 18-19 perweek, about 19-20 per week, about 1-10 per week, about 10-20 per week,about 20-30 per week, about 30-40 per week, about 40-50 per week, about50-60 per week, or more, e.g. as compared to baseline, placebo, or someother appropriate control (including an active control, such as astimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the total numberof cataplexy attacks (partial+complete) by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%,about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%,about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%,about 75-100%, about 40-60%, at least about 1 per week, at least about 2per week, at least about 3 per week, at least about 4 per week, at leastabout 5 per week, at least about 6 per week, at least about 7 per week,at least about 8 per week, at least about 9 per week, at least about 10per week, at least about 12 per week, at least about 14 per week, atleast about 16 per week, at least about 18 per week, at least about 20per week, at least about 22 per week, at least about 24 per week, atleast about 26 per week, at least about 28 per week, at least about 30per week, at least about 40 per week, at least about 50 per week, atleast about 60 per week, at least about 70 per week, at least about 80per week, at least about 90 per week, at least about 100 per week, atleast about 110 per week, at least about 120 per week, at least about130 per week, at least about 140 per week, about 10-20 per week, about12-18 per week, about 14-16 per week, about 1-2 per week, about 2-3 perweek, about 3-4 per week, about 4-5 per week, about 5-6 per week, about6-7 per week, about 7-8 per week, about 8-9 per week, about 9-10 perweek, about 10-11 per week, about 11-12 per week, about 12-13 per week,about 13-14 per week, about 14-15 per week, about 15-16 per week, about16-17 per week, about 17-18 per week, about 18-19 per week, about 19-20per week, about 1-10 per week, about 10-20 per week, about 20-30 perweek, about 30-40 per week, about 40-50 per week, about 50-60 per week,about 60-70 per week, about 70-80 per week, about 80-90 per week, about90-100 per week, about 100-120 per week, about 120-140 per week, ormore, e.g. as compared to baseline, placebo, or some other appropriatecontrol (including an active control, such as a stimulant (e.g.methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may result in the proportionof patients achieving a 50% or greater reduction in the weekly number ofcataplexy attacks that is about 60-95%, about 70-80%, or about 74-78%,e.g. as compared to baseline, placebo, or some other appropriate control(including an active control, such as a stimulant (e.g. methylphenidate,an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the ESS score byat least about 10%, at least about 20%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, at least about 95%, about 1-10%,about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%,about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%,about 25-50%, about 50-75%, or about 75-100%, at least about 1, at leastabout 2, at least about 3, at least about 4, at least about 5, at leastabout 6, at least about 7, at least about 8, at least about 9, at leastabout 10, at least about 11, at least about 12, at least about 13, atleast about 14, at least about 15, at least about 16, at least about 17,at least about 18, at least about 19, at least about 20, at least about21, at least about 22, at least about 23, about 24, about 1-2, about2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9,about 9-10, about 10-11, about 11-12, about 12-13, about 13-14, about14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20,about 20-21, about 21-22, about 22-23, about 23-24, about 1-4, about4-8, about 8-12, about 12-16, about 16-20, about 20-24, about 1-12, orabout 12-24 e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the weekly numberof inadvertent naps by at least about at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about75-100%, about 20-40%, about 30-35%, or about 30-33%, e.g. as comparedto baseline, placebo, or some other appropriate control (including anactive control, such as a stimulant (e.g. methylphenidate, anamphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the MWT score byat least about 10%, at least about 20%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, at least about 95%, about 1-10%,about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%,about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%,about 25-50%, about 50-75%, or about 75-100%, at least about 1 minute,at least about 2 minutes, at least about 3 minutes, at least about 4minutes, at least about 5 minutes, at least about 6 minutes, at leastabout 7 minutes, at least about 8 minutes, at least about 9 minutes, atleast about 10 minutes, at least about 11 minutes, at least about 12minutes, at least about 13 minutes, at least about 14 minutes, at leastabout 15 minutes, at least about 16 minutes, at least about 17 minutes,at least about 18 minutes, at least about 19 minutes, at least about 20minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes,about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes,about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about18-19 minutes, about 19-20 minutes, about 20-21 minutes, about 21-22minutes, about 22-23 minutes, about 23-24 minutes, about 24-26 minutes,about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20minutes, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may improve cognitivefunction, e.g. over a 2-week period, as measured by the Ability toConcentrate item of the NSAQ. For example, the improvement in theability to concentrate score may be at least about −0.1, at least about−0.2, at least about −0.3, about −0.05 to about −0.5, about −0.05 toabout −0.2, about −0.2 to about −0.3, about 0.3 to about −0.4, or about0.4 to about −0.5, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI). In someembodiments, the number of patients having an ability to concentratethat is “very good” or “good” may be at least about 20%, at least about30%, at least about 40%, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 90%, at least about95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about25-50%, about 50-75%, or about 75-100%, about 40-60%, about 40-45%, e.g.as compared to baseline, placebo, or some other appropriate control(including an active control, such as a stimulant (e.g. methylphenidate,an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “average,” “poor,” or “very poor,”and two weeks after the start of the treatment, the human being has anability to concentrate that is “good” or “very good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “average,” and two weeks after thestart of the treatment, the human being has an ability to concentratethat is “good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “average,” and two weeks after thestart of the treatment, the human being has an ability to concentratethat is “very good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “poor,” and two weeks after thestart of the treatment, the human being has an ability to concentratethat is “good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “poor,” and two weeks after thestart of the treatment, the human being has an ability to concentratethat is “very good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “very poor,” and two weeks afterthe start of the treatment, the human being has an ability toconcentrate that is “good.”

In some embodiments, prior to the start of treatment, the human beinghas an ability to concentrate that is “very poor,” and two weeks afterthe start of the treatment, the human being has an ability toconcentrate that is “very good.”

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may improve sleep quality.For example, the patient may report improved sleep quality. In someembodiments, the number of patients reporting improved sleep quality maybe at least about 20%, at least about 30%, at least about 40%, at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, about 40-60%, about 42-47%, e.g. as compared to baseline,placebo, or some other appropriate control (including an active control,such as a stimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the number ofawakenings at night, e.g. as reported by the patient. For example, thenumber of patients reporting a reduction in the number of awakenings atnight may be at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, about 20-30%, about30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, about 40-60%, about 42-47%, e.g. as compared to baseline,placebo, or some other appropriate control (including an active control,such as a stimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the number ofsleep paralysis episodes, e.g. as reported by the patient. For example,the number of patients having a reduction in the number of sleepparalysis episodes may be at least about 20%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 95%, about20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about50-75%, or about 75-100%, about 50-70%, about 52-57%, e.g. as comparedto baseline, placebo, or some other appropriate control (including anactive control, such as a stimulant (e.g. methylphenidate, anamphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the number ofhypnagogic hallucinations, e.g. as reported by the patient. For example,the number of patients having a reduction in the number of hypnagogichallucinations may be at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, about 20-30%, about 30-40%, about 40-50%,about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%,about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%,about 35-45%, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the cataplexyscore on the UNS by at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, at leastabout 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, atleast about 1, at least about 2, at least about 3, at least about 4, atleast about 5, at least about 6, at least about 7, at least about 8, atleast about 9, at least about 10, about 11, about 2-3, about 3-4, about4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4,about 4-6, about 6-8, about 8-10, about 10-11, about 2-6, or about 6-10,about 5-11, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may increase sleep latencyon the MSLT by at least about 30%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 95%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 50-75%, or about 75-100%, at least about 1 minute,at least about 2 minutes, at least about 3 minutes, at least about 4minutes, at least about 5 minutes, at least about 6 minutes, at leastabout 7 minutes, at least about 8 minutes, at least about 9 minutes, atleast about 10 minutes, at least about 11 minutes, at least about 12minutes, at least about 13 minutes, at least about 14 minutes, at leastabout 15 minutes, at least about 16 minutes, at least about 17 minutes,at least about 18 minutes, at least about 19 minutes, at least about 20minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes,about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes,about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about18-19 minutes, about 19-20 minutes, about 1-4 minutes, about 4-8minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes,about 1-10 minutes, or about 10-20 minutes, e.g. as compared tobaseline, placebo, or some other appropriate control (including anactive control, such as a stimulant (e.g. methylphenidate, anamphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the PatientGlobal Impression of Severity (PGI-S) score by at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, about 1-10%, about 10-20%, about20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about50-75%, about 75-100%, at least about 0.1, at least about 0.5, at leastabout 1, at least about 1.5, at least about 2, at least about 2.5, atleast about 3, at least about 3.5, about 0.1-0.5, about 0.5-1, about1-1.5, about 1.5-2, about 2-2.5, about 2.5-3, about 3-3.5, or about3.5-4, e.g. as compared to baseline, placebo, or some other appropriatecontrol (including an active control, such as a stimulant (e.g.methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may result in a PatientGlobal Impression of Change (PGI-C) score that is about 1-2, 2-3, or3-4, or is reduced by at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, at leastabout 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, atleast about 0.5, at least about 1, at least about 2, at least about 3,at least about 4, at least about 5, about 0.5-1, about 1-2, about 2-3,about 3-4, about 4-5, or about 5-6, e.g. as compared to placebo, or someother appropriate control (including an active control, such as astimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce the HamiltonDepression Rating Scale (HAM-D) score by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%,about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%,about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, orabout 75-100%, at least about 1, at least about 2, at least about 3, atleast about 4, at least about 5, at least about 6, at least about 7, atleast about 8, at least about 9, at least about 10, at least about 11,at least about 12, at least about 13, at least about 14, at least about15, at least about 16, at least about 17, at least about 18, at leastabout 19, at least about 20, at least about 21, at least about 22, atleast about 23, at least about 30, at least about 40, about 1-2, about2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9,about 9-10, about 10-11, about 11-12, about 12-13, about 13-14, about14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20,about 20-21, about 21-22, about 22-23, about 23-27, about 27-30, about30-35, about 35-40, about 40-45, about 45-50, about 1-4, about 4-8,about 8-12, about 12-16, about 16-20, about 20-24, about 24-30, about30-40, about 40-50. about 1-12, about 12-24, about 24-36, or about 36-50e.g. as compared to baseline, placebo, or some other appropriate control(including an active control, such as a stimulant (e.g. methylphenidate,an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce nightmares orunpleasant dreams (such as frequent nightmares and frequent unpleasantdreams) by at least about 1%, at least about 10%, at least about 20%, atleast about 30%, at least about 40%, at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90%, atleast about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%,about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%,about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce hallucinations byat least about 1%, at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, at leastabout 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g.as compared to baseline, placebo, or some other appropriate control(including an active control, such as a stimulant (e.g. methylphenidate,an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce sleep paralysisby at least about 1%, at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, at leastabout 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g.as compared to baseline, placebo, or some other appropriate control(including an active control, such as a stimulant (e.g. methylphenidate,an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclicantidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reduce disturbednocturnal sleep by at least about 1%, at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about75-100%, e.g. as compared to baseline, placebo, or some otherappropriate control (including an active control, such as a stimulant(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodiumoxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reducenarcolepsy-related accidents by at least about 1%, at least about 10%,at least about 20%, at least about 30%, at least about 40%, at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, about 1-10%, about 10-20%, about20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about50-75%, or about 75-100%, e.g. as compared to baseline, placebo, or someother appropriate control (including an active control, such as astimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reducenarcolepsy-related injuries by at least about 1%, at least about 10%, atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, about 1-10%, about 10-20%, about20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about50-75%, or about 75-100%, e.g. as compared to baseline, placebo, or someother appropriate control (including an active control, such as astimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

In some embodiments, administering an antidepressant, including anorepinephrine inhibitor such as reboxetine may reducenarcolepsy-related fatal accidents by at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 40%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%,about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%,about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%,about 50-75%, or about 75-100%, e.g. as compared to baseline, placebo,or some other appropriate control (including an active control, such asa stimulant (e.g. methylphenidate, an amphetamine), modafanil,armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or anSNRI).

Reboxetine (with the structure shown below) is a highly selective andpotent norepinephrine reuptake inhibitor that has the potential toaddress the key symptoms of narcolepsy, such as cataplexy or EDS. Unlikeexisting treatments for narcolepsy, reboxetine is not a controlledsubstance. Thus, the treatment with reboxetine would not be scheduled.

Unless otherwise indicated, any reference to a compound herein, such asreboxetine, by structure, name, or any other means, includespharmaceutically acceptable salts; free acids or bases; alternate solidforms, such as polymorphs, solvates, hydrates, etc.; tautomers;enantiomers; deuterium modified compounds, such as deuterium modifiedreboxetine; or any chemical species that may rapidly convert to acompound described herein under conditions in which the compounds areused as described herein.

In some embodiments, reboxetine is in a salt form, a free base form, ormay contain an excess (e.g. at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 97%, or at least 99%) of(+)-reboxetine or an excess (e.g. at least 60%, at least 70%, at least80%, at least 90%, at least 95%, at least 97%, or at least 99%) of(−)-reboxetine.

For treatment of narcolepsy, the reboxetine may be administered in amanner that results in 1) a first local maximum in reboxetine plasmaconcentration and 2) a second local maximum in reboxetine plasmaconcentration.

There are many potential ways that reboxetine could be administered in amanner that results in a first local maximum in reboxetine plasmaconcentration and a second local maximum in reboxetine plasmaconcentration. A local maximum described herein is a maximum of a plasmaconcentration in a time period of interest in an individual patient,which is not necessarily the C_(max). The local maximum may be lower orthe same as C_(max). One potential way to administer reboxetine in amanner that results in a first local maximum in reboxetine plasmaconcentration and a second local maximum in reboxetine plasmaconcentration is to administer a first dosage form containing reboxetineand, at a later time, a second dosage form containing reboxetine. Thedoses are administered at times that result in a first local maximum inreboxetine plasma concentration and a second local maximum in reboxetineplasma concentration. For example, the second dosage form may beadministered less than half a day after the first dosage form, e.g.about 1-8 hours, about 8-12 hours, about 2-6 hours, about 1-2 hours,about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours,about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours,about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, orabout 7-10 hours, after the first dosage form, or any time period in arange bounded by any of these values.

Another method involves administering a single dosage form comprising afirst release component and a second release component. Both the firstrelease component and the second release component comprise reboxetine.

In some embodiments, the first dosage form administered in a day, theonly dosage form administered during the day, or the first of two ormore dosage forms administered during the day, is administered shortlyafter waking, such as within about 3 hours, within about 2 hours, withinabout 1.5 hours, within about 1 hour, within about 30 minutes, or withinabout 15 minutes of waking from an overnight sleep.

For a single dosage form comprising a first release component and asecond release component that is administered in a day, the firstrelease component may release reboxetine, may begin releasingreboxetine, or may result in a first local maximum in the plasmaconcentration of reboxetine, about 0-30 minutes, about 30-60 minutes,about 60-90 minutes, or about 90-120 minutes after the dosage form isorally administered, or any time period in a range bounded by any ofthese values. The second release component may release reboxetine afterthe first release component releases reboxetine, or may cause anincrease of reboxetine plasma concentration or a second local maximum inthe plasma concentration of reboxetine, that is about 1-10 hours, about2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5hours, about 5-6 hours, about 6-7 hours, about 1-3 hours, about 2-4hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8hours, or about 7-10 hours after reboxetine is first released from thefirst release component, or after the first local maximum in the plasmaconcentration of reboxetine, or at any time in a range bounded by any ofthese values.

The first release component and the second release component may beincorporated into one single dosage form (such as a pill, tablet,capsule, caplet, or cachou). In one embodiment, the first releasecomponent would be located in one of the outer layers of the dosage formand the second release component would be located in one of the innerlayers of the same dosage form.

In another embodiment, the first release component is located in a firstlayer of the dosage form, and the second release component is located ina second layer of the same dosage form. The two layers are distinct andmay or may not be in contact with one another. In some embodiments, thetwo layers are stacked on top of one another and physically bound in abi-layer structure (e.g. where the largest surfaces of the two layerscontact one another, or the layers are thin compared to the otherdimensions of the layers). In some embodiments, the two layers arepositioned next to one another and physically bound in a bi-layerstructure (e.g. where the layers are thicker than other dimensions ofthe layers).

In another embodiment, the first release component and the secondrelease component may be constructed separately in their own specificgranules, particles, or the like, wherein the first release componentparticles are formulated to release reboxetine before the second releasecomponent particles release reboxetine and wherein both the firstrelease component particles and the second release component particlesare combined together into a single dosage form, such as a capsule,pill, tablet, caplet, cachou or the like, and the two release componentsmay or may not be physically bound to one another.

In some embodiments, the first local maximum plasma concentration ofreboxetine occurs about 1-30 minutes, about 30-60 minutes, about 1-2hours, about 2-3 hours, or about 3-4 hours after the single dosage formor the first dosage form is administered, or at any time in a rangebounded by any of these values. Generally, the second local maximumplasma concentration of reboxetine occurs less than half a day after thefirst local maximum plasma concentration of reboxetine, such as about1-10 hours, about 1-2 hours, about 2-6 hours, about 2-3 hours, about 3-4hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, after thefirst local maximum plasma concentration of reboxetine, or any timeperiod in a range bounded by any of these values.

For dosage forms containing a first release component and a secondrelease component, the first release component is associated with thefirst local maximum in reboxetine plasma concentration in that the firstrelease component releases the reboxetine that contributes to the firstlocal maximum in reboxetine plasma concentration. For example, the firstrelease component could release reboxetine faster or sooner than thesecond release component, so that most of the reboxetine contributing tothe first local maximum plasma concentration of reboxetine that wasreleased from the first release component.

For dosage forms containing a first release component and a secondrelease component, the second release component is associated with thesecond local maximum in reboxetine plasma concentration in that thesecond release component releases the reboxetine that contributes to thesecond local maximum in reboxetine plasma concentration. For example,the second release component could delay release of its reboxetine sothat at a time when the reboxetine plasma concentration is decreasingafter the first local maximum, the second release component releases asufficient amount of reboxetine to again increase the plasmaconcentration of reboxetine so that the second local maximum inreboxetine plasma concentration is achieved.

For dosage forms containing a first release component and a secondrelease component, any suitable amount of reboxetine may be present inthe first release component, such as about 1-10 mg, about 0.1-2 mg,about 0.5-1.5 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol,about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol,about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol,about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, orany amount in a range bounded by any of these values.

For dosage forms containing a first release component and a secondrelease component, any suitable amount of reboxetine may be present inthe second release component, such as about 0.1-2 mg, about 0.5-1.5 mg,about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about2.5-3.5 mg, about 3-4 mg, about 2-4 mg, about 3-5 mg, about 3.5-4.5 mg,about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 4-6 mg, about 6-7mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 5-7 mg, about 7-10mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in arange bounded by any of these values.

In some embodiments, the first release component may contain morereboxetine than the second release component, such as about 10-20% more,about 20-30% more, or about 30-40% more reboxetine, than the secondrelease component.

The dose of reboxetine may gradually increase over time, such as for 1,2, 3, 4, 5, 6, or 7 days, to a maintenance dose, which is a total dosegiven each day (e.g. a 10 mg maintenance dose could be a once daily 10mg dose, a 6 mg morning dose and a 4 mg afternoon dose, or 5 mg giventwice a day for a total of 10 mg per day). In some embodiments, themaintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg,about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11mg, about 11-14 mg, about 14-17 mg, about 17-20 mg, about 8-10 mg, about8-12 mg, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about0.03-0.033 mmol, about 0.033-0.036 mmol, about 0.036-0.039 mmol, about0.039-0.042 mmol, about 0.042-0.045 mmol, about 0.045-0.048 mmol, about0.048-0.051 mmol, about 0.051-0.054 mmol, about 0.054-0.057 mmol, about0.057-0.06 mmol, about 0.06-0.063 mmol, about 0.063-0.066 mmol, about0.066-0.069 mmol, about 0.006-0.01 mmol, about 0.01-0.02 mmol, about0.02-0.03 mmol, about 0.03-0.04 mmol, about 0.04-0.05 mmol, about0.05-0.06 mmol, about 0.06-0.07 mmol, or about 0.07-0.08 mmol. In someembodiments, a first dose, e.g. administered in the morning, may containmore reboxetine than a second dose administered in a day, e.g.administered in the afternoon. For example, the first dose of the day,e.g. administered in the morning, may have about 10-20% more, about20-30% more, or about 30-40% more reboxetine than the second dose of theday, e.g. administered in the afternoon. The maintenance dose may beadministered for at least about 1 week, at least about 2 weeks, at leastabout 3 weeks, at least about 4 weeks, at least about 5 weeks, at leastabout 6 weeks, at least about 7 weeks, at least about 8 weeks, at leastabout 9 weeks, at least about 10 weeks, at least about 11 weeks, atleast about 12 weeks, at least 4 months, at least 5 months, at leastabout 6 months, at least about 7 months, at least about 8 months, atleast about 9 months, at least about 10 months, at least about 11months, at least about 12 months, at least 1.5 years, at least 2 years,at least about 3 years, at least about 4 years, at least about 5 years,at least about 10 years, at least about 20 years, or longer.

In some embodiments, a patient receives about 110-130 mg of reboxetineover a period of two weeks.

In some embodiments, the first release component provides immediaterelease of reboxetine. In some embodiments, the first release componentprovides delayed release of reboxetine. In some embodiments, the firstrelease component provides sustained release of reboxetine.

In some embodiments, the second release component provides immediaterelease of reboxetine. In some embodiments, the second release componentprovides delayed release of reboxetine. In some embodiments, the secondrelease component provides sustained release of reboxetine.

In some embodiments, the first release component provides immediaterelease of reboxetine, and the second release component provides delayedrelease of reboxetine. In some embodiments, the first release componentprovides immediate release of reboxetine, and the second releasecomponent provides sustained release of reboxetine.

With respect to methods wherein the reboxetine is administered in afirst dosage form containing reboxetine and a second dosage formcontaining reboxetine, any suitable amount of reboxetine may be presentin the first dosage form, such as about 1-10 mg, about 0.1-1 mg, about0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg,about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about0.03-0.033 mmol, or any amount in a range bounded by any of thesevalues.

With respect to methods wherein the reboxetine is administered in afirst dosage form containing reboxetine and a second dosage formcontaining reboxetine, any suitable amount of reboxetine may be presentin the second dosage form, such as about 0.1-1 mg, about 0.1-2 mg, about0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg,about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg,about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg,about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or anyamount in a range bounded by any of these values.

In some embodiments, the first dosage form may contain more reboxetinethan the dosage form, such as about 10-20% more, about 20-30% more, orabout 30-40% more reboxetine than the second dosage form.

In some embodiments, the first dosage form provides immediate release ofreboxetine. In some embodiments, the first dosage form provides delayedrelease of reboxetine. In some embodiments, the first dosage formprovides sustained release of reboxetine.

In some embodiments, the second dosage form provides immediate releaseof reboxetine. In some embodiments, the second dosage form providesdelayed release of reboxetine. In some embodiments, the second dosageform provides sustained release of reboxetine.

With respect to single dosage forms containing both a first releasecomponent and a second release component, in some embodiments, thesingle dosage is administered within two hours of waking from anovernight sleep.

For some embodiments wherein more than one dosage form is given, thefirst dosage form may be administered within two hours of waking from anovernight sleep.

There are many factors that can affect the overall time required for adrug substance such as reboxetine to be fully absorbed and/or reach amaximum plasma concentration in a human being. Some of these factorsinclude a human patient's age, weight, gender, level of stress, stomachcontents, stomach pH level, and the presence of other medications. Thetime required to reach a maximum plasma concentration of the drug suchas reboxetine may also be affected by the time of the day taken the drugsuch as reboxetine and the level of physical activity of the humanpatient. Another factor that can affect the time required to reach amaximum plasma concentration of the drug such as reboxetine is thepresence or absence of a controlled release coating on the drug such asreboxetine.

Controlled release includes: immediate release of drug substance such asreboxetine at a certain time or in a certain area of the body; delayedrelease of a drug substance; sustained release of drug substance at acertain time or place in the body; or an extended release of a drugsubstance such as reboxetine.

Reboxetine is normally rapidly absorbed in human patients, reaching amaximum plasma concentration in about 2-4 hours. To achieve a delay inthe time required to reach a maximum plasma concentration, a controlledrelease coating or mixture may be employed.

Delayed release is a general drug delivery term that describes the formof an oral medication that does not immediately discharge its activedrug component in the mouth or in the stomach of a patient. While theremay be many ways to achieve delayed release, delayed release ofreboxetine may be achieved by completely or partially surrounding thereboxetine, e.g. in the second release component, with a coating orlayer (e.g. an inner controlled release coating) that does notimmediately dissolve when swallowed. For example, the material of thecoating or layer may slowly dissolve in the stomach, and/or slowlydisintegrate by chemical reaction, such as by hydrolysis, in the stomachuntil the layer can no longer prevent the reboxetine from coming intocontact with the gastric fluid.

In some embodiments, the delayed release coating ensures deliverythrough the stomach and into the intestines. Once in the duodenum, thecoating may begin to break down and begin to release reboxetine. In somecases, the reboxetine may be completely released in the duodenum. Insome embodiments, the reboxetine may be partially released in theduodenum, and partially released in the jejunum. In some cases, thereboxetine may be completely released in the jejunum. In some cases, thereboxetine may be partially released in the jejunum and partiallyreleased in the ilium. In some cases, the reboxetine may be completelyreleased in the ilium. In some cases, the reboxetine may be partiallyreleased in the duodenum, the jejunum, and the ilium. In someembodiments, the reboxetine may be partially released in the ilium, andpartially released in the colon. In some cases, the reboxetine may becompletely released in the colon.

The time of the delayed release, e.g. between release of the firstreboxetine component and the second reboxetine component, can beadjusted by using a material that dissolves or disintegrates more orless slowly in the digestive system, adjusting the thickness of thecoating layer or the coating material (e.g. a thicker layer wouldprovide a longer time), and/or by using materials whose properties aresensitive to pH. For example, materials that are less stable to, or moresoluble in, acidic pHs, may dissolve or disintegrate more quickly in thestomach because the stomach pH is lower than the pH in the intestines.Conversely, materials that are stable at low pH, but less stable athigher pH may dissolve or disintegrate later because of the time ittakes the dosage form to travel through the gastrointestinal tract.

A controlled release formulation containing reboxetine can be coatedwith one or more functional or non-functional coatings. Examples offunctional coatings include controlled release polymeric coatings (i.e.controlled release coats), moisture barrier coatings, enteric polymericcoatings, and the like.

A controlled release polymer may be used for both sustained release orfor delayed release, depending upon the structure of the dosage form.For example, interspersing the reboxetine throughout a controlledrelease polymer can provide sustained release, since the drug will bereleased for as long as the polymer is present in the GI tract. Delayedrelease may be achieved by creating a barrier, such as a coating, whichis intended to last for a shorter time (e.g. less than 12 hours, lessthan 10 hours, less than 6 hours, less than 3 hours, etc.), so that whenthe barrier is penetrated, the reboxetine is freely released. Thethickness of the barrier can be used to control the delay time.

Any suitable controlled release polymer may be used, such as acrylicacid and methacrylic acid copolymers and various esters thereof, e.g.methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polyacrylamide, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Other suitable controlled release polymers include polymerizablequaternary ammonium compounds, e.g. quaternized aminoalkyl esters andaminoalkyl amides of acrylic acid and methacrylic acid, for exampleβ-methacryloxyethyltrimethylammonium methosulfate,β-acryloxypropyltrimethylammonium chloride, andtrimethylaminomethylmethacrylamide methosulfate. The quaternary ammoniumatom can also be part of a heterocycle, as inmethacryloxyethylmethylmorpholinium chloride or the correspondingpiperidinium salt, or it can be joined to an acrylic acid group or amethacrylic acid group by way of a group containing hetero atoms, suchas a polyglycol ether group. Further suitable polymerizable quaternaryammonium compounds include quaternized vinyl-substituted nitrogenheterocycles such as methyl-vinyl pyridinium salts, vinyl esters ofquaternized amino carboxylic acids, styryltrialkyl ammonium salts, andthe like. Other polymerizable quaternary ammonium compounds includebenzyldimethylammoniumethylmethacrylate chloride,diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate,N-trimethylammoniumpropylmethacrylamide chloride, andN-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

Delayed release may also be achieved by using a controlled releasepolymer that targets a particular pH, with the understanding that, withproper fasting or feeding, the particular pH could correspond to aparticular time after administration.

For some controlled release polymers, an acrylic or methacrylic polymercomprises one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers (such as those sold by Evonik under thetrademark EUDRAGIT® RS and RL) are fully polymerized copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. The ammonium groups are appended to the ester portionof the methacrylate (as 2-trimethylammonium-ethyl esters). The chargedammonium groups in these polymers make them insoluble and highlypermeable with pH-independent swelling. These properties make thesepolymers useful for customized, time-controlled release of the coateddrug. In order to obtain a desirable dissolution profile for a giventherapeutically active agent, such as reboxetine, two or more ammoniomethacrylate copolymers having differing physical properties can beincorporated. For example, it is known that by changing the molar ratioof the pre-polymerized materials containing quaternary ammonium groupsto pre-polymerized materials containing the uncharged, neutralmethacrylic or acrylic esters, the permeability properties of theresultant coating can be modified.

In other embodiments, the control releasing coat further includes apolymer whose permeability is pH dependent, such as anionic polymerssynthesized from methacrylic acid and methacrylic acid methyl ester.Such polymers are commercially available, e.g., from Evonik, under thetradename EUDRAGIT® L and EUDRAGIT® S. The ratio of free carboxyl groupsto the esters is known to be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S.EUDRAGIT® L is insoluble in acids and pure water but becomesincreasingly permeable above pH 5.0. This makes EUDRAGIT® L appropriatefor targeting release of the coated drug substance such as coatedreboxetine in the duodenum and the jejunum of the small intestine. Thus,a EUDRAGIT® L coated drug substance may achieve a delay in maximumplasma concentration, relative to an uncoated or immediate release drugsubstance (e.g. reboxetine in a first release component), of about 30min to about 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5hours, about 2.5-3 hours, or about 3.5-4 hours.

EUDRAGIT® S is similar to EUDRAGIT® L, except that it becomesincreasingly permeable above pH 7. This makes EUDRAGIT® S appropriatefor targeting release of the coated drug substance such as coatedreboxetine in the ileum of the small intestine and also the colon. Thus,a EUDRAGIT® S coated drug substance may achieve a delay in maximumplasma concentration, relative to an uncoated or immediate release drugsubstance (e.g. reboxetine in a first release component), of about 1-2hours, about 2-3 hours, about 3-4 hours about 4-5 hours, about 5-6hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10hours.

A hydrophobic acrylic polymer coating can also include a polymer whichis based on dimethylaminoethyl methacrylate and neutral methacrylic acidesters (such as EUDRAGIT® E, commercially available from Evonik).EUDRAGIT® E is not soluble in saliva (making it useful for taste andodor masking) but is soluble in gastric fluid with pH 5 or less, whichprovides an immediate release of drug product in the stomach. Reboxetinesurrounded with a EUDRAGIT® E coating may release reboxetine, may beginreleasing reboxetine, or may reach a first local maximum in the plasmaconcentration of reboxetine, at a time of about 0-30 minutes, 30-60minutes, 60-90 minutes, or 90-120 minutes after the dosage form isorally administered, or any time period in a range bounded by any ofthese values.

A hydrophobic acrylic polymer coating can include a neutral copolymerbased on a poly methacrylate, such as EUDRAGIT® NE (NE=neutral ester),commercially available from Evonik. EUDRAGIT® NE 30D lacquer films areinsoluble in water and digestive fluids, but permeable and swellable,providing another option for time-controlled release. EUDRAGIT® NE has apH-independent sustained release effect that can release a drugsubstance such as reboxetine over a period of time, or may delay releasefor a period of time, wherein the time of release or delay is about 1-24hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6hours.

In some embodiments, the control releasing coat comprises a polymercomprising ethyl acrylate and methyl methacrylate in a 2:1 ratio(KOLLICOAT® EMM 30 D, BASF). KOLLICOAT® EMM 30 D has a pH-independentsustained release effect that can release a drug substance such asreboxetine over a period of time, or may delay release for a period oftime, wherein the time of release or delay is about 1-24 hours, about1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the control releasing coat comprises a polyvinylacetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfatesuch as KOLLICOAT® SR30D (BASF). The dissolution profile can be alteredby changing the relative amounts of different acrylic resin lacquersincluded in the coating. Also, by changing the molar ratio ofpolymerizable permeability-enhancing agent (e.g., the quaternaryammonium compounds) to the neutral methacrylic esters, the permeabilityproperties (which affect the dissolution profile) of the resultantcoating can be modified. KOLLICOAT® SR30D is another coating with apH-independent sustained release effect that can release a drugsubstance such as reboxetine over a period of time, or may delay releasefor a period of time, wherein the time of release or delay is about 1-24hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6hours, about 1-4 hours, or about 1-2 hours.

In some embodiments, the control releasing coat comprisesethylcellulose, which can be used as a dry polymer (such as ETHOCEL™,Dow Chemical Company) solubilized in organic solvent prior to use, or asan aqueous dispersion. One suitable commercially-available aqueousdispersion of ethylcellulose is Aquacoat® (Danisco). Aquacoat® ECD(ethylcellulose aqueous dispersion), Aquacoat® ARC (alcohol-resistantethylcellulose aqueous dispersion), and Aquacoat® CPD (cellulose acetatephthalate aqueous dispersion) are all commercially available controlledrelease coatings. Another suitable aqueous dispersion of ethylcelluloseis commercially available as Surelease® (Colorcon, Inc.). This productcan be prepared by incorporating plasticizer into the dispersion duringthe manufacturing process. A hot melt of a polymer, plasticizer (e.g.dibutyl sebacate), and stabilizer (e.g. oleic acid) may be mixed andprepared as a homogeneous mixture, which is then diluted with analkaline solution to obtain an aqueous dispersion which can be applieddirectly onto substrates. These coatings have a pH-independent sustainedrelease effect that can release a drug substance such as reboxetine overa period of time, or may delay release for a period of time, wherein thetime of release or delay is about 1-24 hours, about 1-18 hours, about1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about1-2 hours.

Other examples of polymers that can be used in the control-releasingcoat include cellulose acetate phthalate, cellulose acetate trimaleate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels andgel-forming materials, such as carboxyvinyl polymers, sodium alginate,sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethylcellulose, gelatin, starch, and cellulose based cross-linked polymers inwhich the degree of crosslinking is low so as to facilitate adsorptionof water and expansion of the polymer matrix, hydroxypropyl cellulose,hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilicpolymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic andcationic hydrogels, zein, polyamides, polyvinyl alcohol having a lowacetate residual, a swellable mixture of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene,propylene or isobutylene, pectin (molecular weight 30 k to 300 k),polysaccharides such as agar, acacia, karaya, tragacanth, algins andguar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100k to 5000 k, Dow), AQUA KEEP® acrylate polymers (composed of mainlyacrylic acid polymer, sodium salt), diesters of polyglucan, crosslinkedpolyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymerssuch as polysaccharides, methyl cellulose, sodium or calciumcarboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethylcellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulosepropionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acidesters, polyacrylamide, polyacrylic acid, natural gums, lecithins,pectin, alginates, ammonia alginate, sodium, calcium, potassiumalginates, propylene glycol alginate, agar, and gums such as arabic,karaya, locust bean, tragacanth, carrageenan, guar, xanthan,scleroglucan and mixtures and blends thereof.

In some embodiments, the dosage forms of reboxetine are coated withpolymers in order to facilitate mucoadhesion within the gastrointestinaltract. Non-limiting examples of polymers that can be used formucoadhesion include carboxymethylcellulose, polyacrylic acid, Carbopol™(Lubrizol), polycarbophil, gelatin and other natural or syntheticpolymers.

The polymeric coatings of the present disclosure may be any one of thedescribed coatings or may be a combination of two or more of thedescribed coatings to achieve the desired release profiles of therelease of reboxetine.

In addition to the modified release dosage forms described herein, othermodified release technologies known to those skilled in the art can beused in order to achieve the modified release formulations of thepresent disclosure, i.e., formulations which provide a mean T_(max) ofthe drug and/or other pharmacokinetic parameters described herein whenadministered e.g., orally or by other mode of administration to humanpatients. Such formulations can be manufactured as a modified releaseoral formulation in a suitable tablet or multiparticulate formulationknown to those skilled in the art. In either case, the modified releasedosage form can optionally include a controlled release carrier which isincorporated into a matrix along with the drug, or which is applied as acontrolled release coating.

Any dosage form comprising an effective amount of reboxetine may furthercomprise a binder, a lubricant, and other conventional inert excipients.

A binder (also sometimes called adhesive) can be added to a drug-fillermixture to increase the mechanical strength of the granules and tabletsduring formation. Binders can be added to the formulation in differentways: (1) as a dry powder, which is mixed with other ingredients beforewet agglomeration, (2) as a solution, which is used as agglomerationliquid during wet agglomeration, and is referred to as a solutionbinder, and (3) as a dry powder, which is mixed with the otheringredients before compaction. In this form the binder is referred to asa dry binder. Solution binders are a common way of incorporating abinder into granules. In certain embodiments, the binder used in thetablets is in the form of a solution binder. Non-limiting examples ofbinders useful include hydrogenated vegetable oil, castor oil, paraffin,higher aliphatic alcohols, higher aliphatic acids, long chain fattyacids, fatty acid esters, wax-like materials such as fatty alcohols,fatty acid esters, fatty acid glycerides, hydrogenated fats,hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobicand hydrophilic polymers having hydrocarbon backbones, and mixturesthereof. Specific examples of water-soluble polymer binders includemodified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives(e.g. hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose(HPC)), polyvinyl alcohol and mixtures thereof. Any suitable amount ofbinder may be present, such as about 0.5-5%, about 5-10%, about 10-15%,about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, orabout 3% by weight of the tablet dry weight. In some embodiments, thebinder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease anyfriction that occurs between the solid and the die wall during tabletmanufacturing. High friction during tableting can cause a series ofproblems, including inadequate tablet quality (capping or evenfragmentation of tablets during ejection, and vertical scratches ontablet edges) and may even stop production. Accordingly, lubricants maybe added to tablet formulations. Non-limiting examples of lubricantsuseful include glyceryl behenate, stearic acid, hydrogenated vegetableoils (such as hydrogenated cottonseed oil (STEROTEX®, hydrogenatedsoybean oil (STEROTEX® HM) and hydrogenated soybean oil & castor wax(STEROTEX® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450,suitably 4000, and higher), magnesium stearate, glyceryl monostearate,stearic acid, polyethylene glycol, ethylene oxide polymers (for example,available under the registered trademark CARBOWAX® from Union Carbide,Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate,sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica,mixtures thereof and others as known in the art. In some embodiments,the lubricant is glyceryl behenate (for example, COMPRITOL® 888). Anysuitable amount of binder may be present, such as about 0.5-5%, about5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5-25%, about0.5-15%, about 1-6%, or about 3% by weight of the tablet dry weight.

In some embodiments, reboxetine is administered once a day or twice aday for at least about 3 weeks, at least about 4 weeks, at least about 5weeks, at least about 6 weeks, at least about 7 weeks, at least about 8weeks, at least about 9 weeks, at least about 10 weeks, at least about11 weeks, at least about 12 weeks, at least about 4 months, at leastabout 5 months, at least about 6 months, at least about 7 months, atleast about 8 months, at least about 9 months, at least about 10 months,at least about 11 months, at least about 12 months, at least 1.5 years,at least 2 years, at least about 3 years, at least about 4 years, atleast about 5 years, about 0.1-5 years, about 5-10 years, at least about10 years, about 10-15 years, at least about 15 years, about 15-20 years,at least about 20 years, or longer.

An example, not as an attempt to limit the scope of the disclosure, of auseful composition for a dosage form containing about 5-10 mg ofreboxetine is shown in Table 1 below:

TABLE 1 Example of dosage form of reboxetine Component Amount (wt/wt)reboxetine 30-70% lubricant  1-10% diluent 20-70% disintegrant  1-10%

Treatment of narcolepsy with cataplexy with reboxetine in the dosageforms described herein may not have significant side effects as theexisting treatment options. Treatment of narcolepsy with cataplexy withreboxetine in the dosage forms described herein may be well tolerated inmammals such as human beings.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising one or more units of a dosage form (e.g. about 1-30, about30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about360-720 units of a dosage form), wherein a unit of the dosage formcomprises about 0.1-5 mg of reboxetine and instructions to use thepharmaceutical composition to treat narcolepsy with cataplexy in a humanbeing.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising one or more units of a dosage form (e.g. about 1-30, about30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about360-720 units of a dosage form), wherein a unit of the dosage formcomprises about 5-10 mg of reboxetine and instructions to use thepharmaceutical composition to treat narcolepsy with cataplexy in a humanbeing.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising one or more units of a dosage form (e.g. about 1-30, about30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about360-720 units of a dosage form), wherein a unit of the dosage formcomprises about 10-15 mg of reboxetine and instructions to use thepharmaceutical composition to treat narcolepsy with cataplexy in a humanbeing.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising one or more units of a dosage form (e.g. about 1-30, about30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about360-720 units of a dosage form), wherein a unit of the dosage formcomprises about 15-20 mg of reboxetine and instructions to use thepharmaceutical composition to treat narcolepsy with cataplexy in a humanbeing.

Some embodiments include a kit comprising a pharmaceutical compositioncomprising one or more units of a dosage form (e.g. about 1-30, about30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about360-720 units of a dosage form), wherein a unit of the dosage formcomprises about 5-20 mg of reboxetine and instructions to use thepharmaceutical composition to treat narcolepsy with cataplexy in a humanbeing.

EXAMPLES Example 1

A 40 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the number of cataplexy attackshave decreased by 10-30%.

Example 2

A 20 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the number of cataplexy attackshave decreased by 30-60%.

Example 3

A 60 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the number of cataplexy attackshave decreased by 60-100%.

Example 4

A 50 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the ESS score has decreased by10-30%.

Example 5

A 25 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the ESS score has decreased by30-60%.

Example 6

A 47 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the ESS score has decreased by60-100%.

Example 7

A 19 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the MWT score has decreased by10-30%.

Example 8

A 42 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the MWT score has decreased by30-60%.

Example 9

A 33 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After one week of treatment, the MWT score has decreased by60-100%.

Example 10

A 54 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the number of cataplexyattacks have decreased by 10-30%.

Example 11

A 27 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the number of cataplexyattacks have decreased by 30-60%.

Example 12

A 52 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the number of cataplexyattacks have decreased by 60-100%.

Example 13

A 66 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the ESS score has decreased by10-30%.

Example 14

A 34 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the ESS score has decreased by30-60%.

Example 15

A 35 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the ESS score has decreased by60-100%.

Example 16

A 19 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the MWT score has decreased by10-30%.

Example 17

A 70 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the MWT score has decreased by30-60%.

Example 18

A 57 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the MWT score has decreased by60-100%.

Example 19

A 20 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the HAM-D score has decreasedby 10-30%.

Example 20

A 69 year old male is diagnosed as suffering from narcolepsy withcataplexy. He is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the HAM-D score has decreasedby 30-60%.

Example 21

A 56 year old female is diagnosed as suffering from narcolepsy withcataplexy. She is given reboxetine and instructed to take 5 mg ofreboxetine at 8 am and 5 mg of reboxetine at 1 pm for three weeks. Thepatient is evaluated prior to treatment, and weekly to determine the MWTscore, the number of cataplexy attacks, the PGI-C score, the HAM-Dscore, the ESS score, the NSAQ score, and the ability to concentrate onthe NSAQ. After three weeks of treatment, the HAM-D score has decreasedby 60-100%.

Example 22

A Phase 2, double-blind, randomized, placebo-controlled, crossover,multicenter trial of reboxetine was carried out in patients withnarcolepsy. A total of 21 patients with a diagnosis of narcolepsy withcataplexy were treated for 2 weeks with reboxetine or with placebo,followed by a crossover to the other treatment after a 1-weekdown-titration and washout period. Reboxetine was administered orallytwice daily, with a total daily dose of 8 mg for Week 1 which wasescalated to 10 mg for Week 2. Patients were randomized in a 1:1 ratioeither to treatment with reboxetine followed by placebo (sequence 1), orto treatment with placebo followed by reboxetine (sequence 2). Theaverage number of cataplexy attacks at baseline was 30. Key assessmentswere made daily using an electronic diary. The prespecified primaryendpoint was the change in the weekly number of cataplexy attacks,averaged over the 2-week treatment period (overall treatment effect).Secondary endpoints included changes in the number of inadvertent naps,cognition, and Epworth Sleepiness Scale. Cognition was assessed usingthe Ability to Concentrate item of the Narcolepsy Symptom AssessmentQuestionnaire, a patient reported outcome measure. This item is rated on5-point scale (1=very good to 5=very poor). All analyses were conductedon an intent-to-treat basis.

As shown in FIG. 1, Reboxetine (AXS-12) met the prespecified primaryendpoint by demonstrating a highly statistically significant reductionfrom baseline in the mean weekly number of cataplexy attacks, averagedfor the 2-week treatment period (overall treatment effect), as comparedto placebo (p<0.001). At Week 2, reboxetine (AXS-12) demonstrated a meanreduction of 14.6 cataplexy attacks per week compared to a reduction of2.6 attacks per week for placebo (p=0.002), representing mean reductionsof 48.8% and 8.6% from baseline, respectively. The proportion ofpatients achieving a 50% or greater reduction in the weekly number ofcataplexy attacks was 76.2% for reboxetine (AXS-12), compared to 30.0%for placebo (p=0.003) at Week 2 (FIG. 2). The proportion of patientsachieving a 75% or greater reduction in the weekly number of cataplexyattacks was 42.8% for reboxetine (AXS-12), compared to 10.0% for placebo(p=0.018) at Week 2 (FIG. 3). The improvement in cataplexy was rapidwith reboxetine (AXS-12) demonstrating significant benefit over placeboas early as Week 1 (p<0.001).

Reboxetine significantly improved EDS symptoms compared to placebo, asmeasured by the Epworth Sleepiness Scale (ESS) and by the frequency ofinadvertent naps. As shown in FIG. 4, the improvement on the ESS withreboxetine (AXS-12) treatment was twice that observed with placebo, withreductions from baseline in the ESS score of 6.0 and 3.1, respectivelyfor reboxetine (AXS-12) and placebo (p=0.003). Reboxetine treatmentresulted in a 31.8% mean reduction from baseline in the average weeklynumber of inadvertent naps versus a 5.3% mean reduction for placebo(p<0.001) at Week 2 (FIG. 5). As shown in FIG. 6, reboxetine treatmentresulted in a greater number of patients with 50% or greater reductionin inadvertent naps (38.1%) as compared to placebo (10.0%) Theimprovement in frequency of inadvertent naps was rapid with reboxetine(AXS-12) demonstrating significant benefit over placebo as early as Week1 (p=0.038).

Reboxetine significantly improved cognitive function compared to placeboover the 2-week treatment period as measured by the Ability toConcentrate item of the Narcolepsy Symptom Assessment Questionnaire(NSAQ), which was assessed daily (p<0.001) (FIGS. 7-8). For thisassessment, patients rated their ability to concentrate on a 5-pointscale (1=very good to 5=very poor). At the end of treatment, 42.9% ofpatients had an ability to concentrate that was “good” to “very good”with reboxetine (AXS-12) treatment, compared to 25.0% of patients withplacebo, and 0% of patients at baseline. The improvement in the abilityto concentrate was rapid with reboxetine (AXS-12) demonstratingsignificant improvement over placebo as early as Week 1 (p=0.007).

Reboxetine significantly improved sleep quality, as measured by overallimprovement and by number of awakenings at night, and reducedsleep-related symptoms, as compared to placebo. As shown in FIG. 9,reboxetine (AXS-12) treatment resulted in 45.0% of patients reportingimproved sleep quality versus 5.3% of patients with placebo (p=0.007).Reboxetine treatment resulted in 30.0% of patients reporting a reductionin the number of awakenings at night versus 5.3% of patients withplacebo (p=0.044). Reboxetine treatment also resulted in greaterproportions of patients with reductions in sleep paralysis episodes, andin hypnagogic hallucinations, as compared to placebo (p=ns).

Reboxetine was safe and well tolerated. There were no serious adverseevents reported in the trial, and no discontinuations due to adverseevents. The overall percentage of patients experiencing adverse eventswas 42.9% with reboxetine (AXS-12) and 40.0% with placebo, with the mostcommonly reported adverse events with reboxetine (AXS-12) treatmentbeing anxiety, constipation, and insomnia. The completion rate was 91%for patients randomized to treatment sequence 1 (reboxetine followed byplacebo) and 100% for those randomized to sequence 2 (placebo followedby reboxetine).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of improving the ability to concentrate in a human being having narcolepsy with cataplexy, comprising administering about 8 mg to about 10 mg of reboxetine daily for at least two weeks to a human being in need thereof, wherein, prior to the start of treatment, the human being has an ability to concentrate that is “average,” “poor,” or “very poor,” and two weeks after the start of the treatment, the human being has an ability to concentrate that is “good” or “very good,” as determined by the Ability to Concentrate Item of the Narcolepsy Symptom Assessment Questionnaire.
 2. The method of claim 1, wherein about 4 mg of reboxetine is administered twice a day to the human being for at least one week.
 3. The method of claim 2, wherein about 4 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 4. The method of claim 1, wherein about 6 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 5. The method of claim 1, wherein the human being has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.
 6. The method of claim 1, wherein the human being has a minimum of 7 cataplexy attacks per week prior to receiving reboxetine.
 7. The method of claim 1, wherein the human being has an Epworth Sleepiness Scale score that is greater than 10 prior to receiving reboxetine.
 8. A method of reducing the number of inadvertent naps in a human being having narcolepsy with cataplexy, comprising administering about 8 mg to about 10 mg of reboxetine daily for at least two weeks to a human being in need thereof, wherein two weeks after the start of the treatment, the human being has at least 20% fewer inadvertent naps per week as compared to the week before the patient first receives reboxetine.
 9. The method of claim 8, wherein about 4 mg of reboxetine is administered twice a day to the human being for at least one week.
 10. The method of claim 9, wherein about 4 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 11. The method of claim 8, wherein about 6 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 12. The method of claim 8, wherein the human being has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.
 13. The method of claim 8, wherein the human being has a minimum of 7 cataplexy attacks per week prior to receiving reboxetine.
 14. The method of claim 8, wherein the human being has an Epworth Sleepiness Scale score that is greater than 10 prior to receiving reboxetine.
 15. A method of improving sleep quality in a human being having narcolepsy with cataplexy, comprising administering about 8 mg to about 10 mg of reboxetine daily for at least two weeks to a human being in need thereof, wherein two weeks after the start of the treatment, the human being reports having improved sleep quality as compared to the week before the patient first receives reboxetine.
 16. The method of claim 15, wherein about 4 mg of reboxetine is administered twice a day to the human being for at least one week.
 17. The method of claim 16, wherein about 4 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 18. The method of claim 15, wherein about 6 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 19. The method of claim 15, wherein the human being has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.
 20. The method of claim 15, wherein the human being has a minimum of 7 cataplexy attacks per week prior to receiving reboxetine.
 21. The method of claim 15, wherein the human being has an Epworth Sleepiness Scale score that is greater than 10 prior to receiving reboxetine.
 22. A method of reducing night awakenings in a human being having narcolepsy with cataplexy, comprising administering about 8 mg to about 10 mg of reboxetine daily for at least two weeks to a human being in need thereof, wherein two weeks after the start of the treatment, the human being reports having fewer night awakenings as compared to the week before the patient first receives reboxetine.
 23. The method of claim 22, wherein about 4 mg of reboxetine is administered twice a day to the human being for at least one week.
 24. The method of claim 23, wherein about 4 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 25. The method of claim 22, wherein about 6 mg of reboxetine is administered to the human being in the morning and about 4 mg of reboxetine is administered to the human being in the afternoon for at least one week.
 26. The method of claim 22, wherein the human being has a diagnosis of narcolepsy with cataplexy that meets International Classification of Sleep Disorders, Third Edition criteria.
 27. The method of claim 22, wherein the human being has a minimum of 7 cataplexy attacks per week prior to receiving reboxetine.
 28. The method of claim 22, wherein the human being has an Epworth Sleepiness Scale score that is greater than 10 prior to receiving reboxetine. 